Smad3-Mediated Signals Showing Similarities and Differences Between Epithelial and Mesenchymal Cells in Human Chronic Liver Diseases

Liver fibrosis, representing excessive accumulation of extracellular matrix (ECM) proteins including collagen, occurs in most types of chronic liver disease. Activated hepatic stellate cells (HSC) and portal fibroblasts have been identified as major collagen-producing cells in the injured liver. As a result of chronic liver damage, HSC undergo progressive activation to assume a proliferative and invasive phenotype. In addition to these mesenchymal cells, the liver's epithelial cells, hepatocytes, are involved in hepatic fibrogenesis. Altered transforming growth factor (TGF)-β signaling can promote hepatic fibrogenesis. TGF-β type I receptor and Ras-associated kinases differentially phosphorylate a mediator Smad3 to create distinct phosphorylated forms: C-terminally phosphorylated Smad3 (pSmad3C), linker phosphorylated Smad3 (pSmad3L), and both linker and C-terminally phosphorylated Smad3 (pSmad3L/C). While pSmad3C transmits a cytostatic TGF-β signal in mature hepatocytes, TGF-β signaling enhances growth of activated mesenchymal cells via a cyclin-dependent kinase 4-dependent pSmad3L/C pathway. On the other hand, pro-inflammatory cytokines transmit a fibrogenic signal in both hepatocytes and activated mesenchymal cells through a c-Jun N-terminal kinase-dependent pSmad3L pathway, which participates in deposition of ECM proteins. Linker phosphorylation of Smad3 indirectly prevents Smad3C phosphorylation, pSmad3C-mediated transcription, and the cytostatic effect of TGF-β upon hepatocytes. During progression of human chronic liver diseases, hepatocytes undergo transition from the tumor-suppressive pSmad3C pathway to the fibrogenic pSmad3L pathway. This review summarizes Smad3 phosphoisoform-mediated signals, showing similarities and differences between hepatocytes and mesenchymal cells and emphasizing the fibrogenic function of hepatocytes in human chronic liver disease.